TESTOGEL 16.2 mg/g is indicated in adults as testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests (see 4.4 Special warnings and precautions for use).

4.2 Posology and method of administration

Transdermal use.

Adult and elderly men

The recommended dose is two pump actuations of gel (i.e. 40.5 mg of testosterone) applied once daily at about the same time, preferably in the morning. The daily dose should be adjusted by the doctor depending on the clinical or laboratory response in individual patients, not exceeding four pump actuations or 81 mg testosterone per day. The adjustment of posology should be achieved by increments of one pump actuation of gel.

The dose should be titrated based on the pre-dose morning testosterone blood levels. Steady state blood testosterone levels are reached usually by the second day of treatment with TESTOGEL 16.2 mg/g. In order to evaluate the need to adjust the testosterone dosage, blood testosterone levels should be measured in the morning before application of the product, after the steady state is reached. Testosterone blood levels should be assessed periodically. The dose may be reduced if the testosterone blood levels are raised above the desired level. If the levels are low, the dosage may be increased stepwise, to a daily administration of 81 mg of testosterone (four actuations of gel) per day.

Therapy should be discontinued if the blood testosterone levels consistently exceeds the normal range at the lowest daily dose of 20.25 mg (1.25 g gel, equivalent to one pump actuation) or if blood testosterone levels in the normal range cannot be achieved with the highest dose of 81 mg (5 g gel, equivalent to four pump actuations).

Patient suffering from severe renal or hepatic insufficiency

Please see section 4.4 Special warnings and precautions for use.

Paediatric population

The safety and efficacy of TESTOGEL 16.2mg/g in males under 18 years have not been established.

No data are available.

Method of administration

The application should be administered by the patient himself, onto clean, dry, healthy skin over right and left upper arms and shoulders.

The gel should be simply spread on the skin gently as a thin layer. It is not necessary to rub it on the skin. Allow to dry for at least 3-5 minutes before dressing. Wash hands with soap and water after application, and cover the application site(s) with clothing after the gel has dried. Wash the application site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application site with another person is anticipated. For more information regarding post dose washing see section 4.4 (subsection Potential for testosterone transfer).

Do not apply to the genital areas as the high alcohol content may cause local irritation.

To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first three actuations. It is only necessary to prime the pump before the first dose.

After the priming procedure, fully depress the actuator once for delivering 1.25 g of TESTOGEL 16.2 mg/g into the palm of the hand and then apply to the upper arms and shoulders.

4.3 Contraindications

TESTOGEL 16.2 mg/g is contraindicated:

- in case of known or suspected prostate cancer or breast carcinoma

- in case of known hypersensitivity to testosterone or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

TESTOGEL 16.2 mg/g should be used only if hypogonadism (hyper- and hypogonadotrophic) has been demonstrated and if other aetiology, responsible for the symptoms, has been excluded before treatment is started. Testosterone insufficiency should be clearly demonstrated by clinical features (regression of secondary sexual characteristics, change in body composition, asthenia, reduced libido, erectile dysfunction etc.) and confirmed by two separate blood testosterone measurements. Currently, there is no consensus about age-specific testosterone reference levels. However, it should be taken into account that physiologically testosterone blood levels decrease with age.

Due to interlaboratory variability, all measurements of testosterone should be carried out by the same laboratory.

TESTOGEL 16.2 mg/g is not indicated for treatment of male sterility or impotence.

Prior to testosterone initiation, all patients must undergo a detailed examination in order to exclude a risk of pre-existing prostate cancer. Careful and regular monitoring of the prostate gland and breast must be performed in accordance with recommended methods (digital rectal examination and estimation of serum prostate specific antigen (PSA)) in patients receiving testosterone therapy at least once yearly and twice yearly in elderly patients and at risk patients (those with clinical or familial risk factors).

Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostate hyperplasia.

TESTOGEL 16.2 mg/g should be used with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of blood calcium levels is recommended in these patients.

In patients suffering from severe cardiac, hepatic or renal insufficiency, or ischaemic disease, treatment with testosterone may cause severe complications characterised by oedema with or without congestive cardiac failure. In such case, treatment must be stopped immediately. In addition, diuretic therapy may be required.

TESTOGEL 16.2 mg/g should be used with caution in patients with ischaemic heart disease.

Testosterone may cause a rise in blood pressure and TESTOGEL 16.2 mg/g should be used with caution in men with hypertension.

Testosterone should be used with caution in patients with thrombophilia, as there have been post-marketing reports of thrombotic events in these patients during testosterone therapy.

Testosterone levels should be monitored at baseline and at regular intervals during treatment. Clinicians should adjust the dosage individually to ensure maintenance of eugonadal testosterone levels.

In addition to laboratory analyses of testosterone levels in patients receiving long-term androgen therapy, the following laboratory parameters should also be monitored regularly: haemoglobin, and haematocrit (to detect polycythaemia), liver function tests, and lipid profile.

There is limited experience on the safety and efficacy of the use of TESTOGEL 16.2 mg/g in patients over 65 years of age. Currently, there is no consensus about age specific testosterone reference levels. However, it should be taken into account that physiologically testosterone blood levels are decreasing with age.

TESTOGEL 16.2 mg/g should be used with caution in patients with epilepsy and migraine as these conditions may be aggravated.

There are published reports of increased risk of sleep apnoea in hypogonadal subjects treated with testosterone esters, especially in those with risk factors such as obesity and chronic respiratory disease.

Improved insulin sensitivity may be observed in patients treated with androgens and may require lowering antidiabetics' dosage.

If the patient develops a severe application site reaction, treatment should be re-evaluated and discontinued if necessary.

With large doses of exogenous androgens, spermatogenesis may be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH) which could possibly lead to adverse effects on semen parameters including sperm count.

Gynecomastia occasionally develops and occasionally persists in patients being treated with androgens for hypogonadism.

TESTOGEL 16.2 mg/g should not be used by women due to possibly virilising effects.

The attention of athletes should be drawn to the fact that this proprietary medicinal product contains an active substance (testosterone) that may produce a positive result in doping control tests.

Potential for inadvertent testosterone transfer

If no precautions are taken, testosterone gel can be transferred to other persons by close skin to skin contact at any time after dosing, resulting in increased testosterone serum levels and possibly adverse effects (e.g. growth of facial and/or body hair, deepening of the voice, irregularities of the menstrual cycle in women and premature puberty and genital enlargement in children) in the event of repeated contact (inadvertent androgenisation). If virilisation occurs, testosterone therapy should be promptly discontinued until the cause has been identified.

The physician should inform the patient carefully about the risk of testosterone transfer and about safety instructions (see below). TESTOGEL 16.2 mg/g should not be prescribed in patients with a major risk of non-compliance with safety instructions (e.g. severe alcoholism, drug abuse, severe psychiatric disorders).

The potential risk of transfer is substantially reduced (but not eliminated) by wearing clothes (such as a sleeved shirt) covering the application area. The majority of residual testosterone is removed from the skin surface by washing with soap and water prior to contact.

As a result, the following precautions are recommended:

For the patient:

- wash hands with soap and water after applying the gel

- cover the application area with clothing (such as a sleeved shirt) once the gel has dried

- shower and wash the application site(s) thoroughly with soap and water to remove any testosterone residue before any situation in which close contact is foreseen

For people not being treated with TESTOGEL 16.2 mg/g:

- in the event of contact with an application area that has not been washed or is not covered with clothing, wash the area of skin onto which testosterone may have been transferred as soon as possible using soap and water

- report the development of signs of excessive androgen exposure such as acne or hair modification

According to in vivo absorption studies on testosterone conducted with TESTOGEL 16.2 mg/g, it seems preferable for patients to observe at least 2 hours between gel application and bathing or showering. Occasional baths or showers taken between 2 and 6 hours after application of the gel should not significantly influence the treatment outcome.

To improve partner safety, the patient should be advised, for example, to wash the area with soap for instance during a shower before sexual intercourse or, if not possible, wear clothing such as a shirt or a T-shirt covering the application site during the contact period.

Furthermore, it is recommended to wear clothing covering the application site (such as a sleeved shirt) during contact periods with children, in order to avoid the risk of contamination of children's skin.

Pregnant women must avoid any contact with TESTOGEL 16.2 mg/g application sites. In case of pregnancy of a partner, the patient must pay extra attention to the precautions for use described above (also see section 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Due to changes in anticoagulant activity (increased effect of the oral anticoagulant by modification of hepatic synthesis of coagulation factor and competitive inhibition of plasma protein binding) increased monitoring of the prothrombin time and international normalized ratio (INR) are recommended. Patients receiving oral anticoagulants require close monitoring especially when androgens are started or stopped.

Concomitant administration of testosterone and ACTH or corticosteroids may increase the risk of developing oedema. As a result, these medicinal products should be administered cautiously, particularly in patients suffering from cardiac, renal or hepatic disease.

Interactions with laboratory tests: androgens may decrease levels of thyroxin binding globulin, resulting in decreased T4 serum concentrations and in increased resin uptake of T3 and T4. Free thyroid hormone levels, however, remain unchanged and there is no clinical evidence of thyroid insufficiency.

TESTOGEL 16.2 mg/g is not indicated in pregnant or breast-feeding women, due to potential virilising effects of the foetus.

Pregnant women must avoid any contact with TESTOGEL 16.2 mg/g application sites (see section 4.4). In the event of contact, wash with soap and water as soon as possible.

Spermatogenesis may be reversibly suppressed with TESTOGEL 16.2 mg/g.

4.7 Effects on ability to drive and use machines

TESTOGEL 16.2 mg/g has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most frequently observed clinical adverse drug reactions observed with TESTOGEL 16.2mg/g used at the recommended dosage were psychiatric disorders and skin reactions at the application site.

The table below shows adverse reactions reported in the 182-day, double-blind period of the TESTOGEL 16.2 mg/g Phase III clinical trial and more frequently in the TESTOGEL 16.2 mg/g treated group (n=234) than the placebo treated group (n=40).

Because of the alcohol contained in the product, frequent applications to the skin may cause irritation and dry skin.

The following adverse reactions have been identified during post-approval use of TESTOGEL 16.2 mg/g. Because the adverse experiences are reported voluntarily from a population of uncertain size, it is not possible to estimate reliably their frequency or establish a definite causal relationship to drug exposure.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system www.mhra.gov.uk/yellowcard.

4.9 Overdose

Only one case of acute testosterone overdose following an injection has been reported in the literature. This was a case of a cerebrovascular accident in a patient with a high plasma testosterone concentration of 114 ng/ml (395 nmol/l). It would be most unlikely that such blood testosterone levels would be achieved using the transdermal route.

Treatment of overdose would consist of discontinuation of TESTOGEL 16.2 mg/g together with appropriate symptomatic and supportive care.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Androgens. ATC code: G03B A03.

Endogenous androgens, testosterone, secreted by the testes and its major metabolite DHT, are responsible for the development of the external and internal genital organs and for maintaining the secondary sexual characteristics (stimulating hair growth, deepening of the voice, development of the libido). Androgens have also an effect on protein anabolism, on development of skeletal muscle and body fat distribution and also reduce urinary nitrogen, sodium, potassium, chloride, phosphate and water excretion.

Testosterone reduces the pituitary secretion of gonadotropins.

The effects of testosterone in some target organs arise after peripheral conversion of testosterone to estradiol, which than binds to oestrogen receptors in the target cell nucleus e.g. the pituitary, fat, brain, bone and testicular Leydig cells.

5.2 Pharmacokinetic properties

The percutaneous absorption of testosterone after administration of TESTOGEL 16.2 mg/g lies between 1% and 8.5%.

Following percutaneous absorption, testosterone diffuses into the systemic circulation and provides relatively constant concentrations during the 24 hour cycle.

Blood testosterone levels increase from the first hour after an application, reaching steady state from day two. Daily changes in testosterone levels are then of similar amplitude to those observed during the circadian rhythm of endogenous testosterone. The percutaneous route therefore avoids the blood distribution peaks produced by injections. It does not produce supra-physiological hepatic concentrations of the steroid in contrast to oral androgen therapy.

Administration of 5 g of TESTOGEL 16.2 mg/g produces an average testosterone level increase of approximately 2.3 ng/ml (8.0 nmol/l) in plasma.

When treatment is stopped, testosterone levels start decreasing approximately 24 hours after the last administration. Testosterone levels return to baseline approximately 72 to 96 hours after the final administration.

The major active metabolites of testosterone are dihydrotestosterone and oestradiol.

Testosterone is excreted mostly in urine as conjugated testosterone metabolites and a small amount is excreted unchanged in the faeces.

In the phase III double blind study at the end of a 112 day treatment period, during which the dose of TESTOGEL 16.2 mg/g could be titrated based on total testosterone concentrations, 81.6% (CI 75.1-87.0%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl). In patients on a daily TESTOGEL 16.2 mg/g dose the average (±SD) daily testosterone concentration on day 112 (Cav) was 561 (±259) ng/dl, mean Cmax was 845 (±480) ng/dl and mean Cmin was 334 (±155) ng/dl. The corresponding concentrations on Day 182 (double blind period) were Cav 536 (±236) ng/dl, mean Cmax 810 (±497) ng/dl and mean Cmin 330 (±147) ng/dl.

In the phase III open label study at the end of a 264 day treatment period, during which the dose of TESTOGEL 16.2 mg/g could be titrated based on total testosterone concentrations, 77 % (CI 69.8-83.2%) of men had total testosterone levels within the normal range for eugonadal young men (300 -1000 ng/dl).

Testosterone has been found to be non-mutagenic in vitro using the reverse mutation model (Ames test) or Chinese hamster ovary cells. A relationship between androgen treatment and certain cancers has been found in studies on laboratory animals. Experimental data in rats have shown increased incidences of prostate cancer after treatment with testosterone.

Sex hormones are known to facilitate the development of certain tumours induced by known carcinogenic agents. The importance of these findings and the actual risk in human beings is unknown.

The administration of exogenous testosterone has been reported to suppress spermatogenesis in the rat, dog and non-human primates, which was reversible on cessation of the treatment.

6. Pharmaceutical particulars

6.1 List of excipients

Carbomer 980

Isopropyl myristate

Ethanol 96%

Sodium hydroxide

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Multi-dose container (comprised of a polypropylene canister with an LDPE lined pouch) with metering pump that contains 88 g gel and delivers a minimum of 60 doses.